Mitogen-activated protein kinase (MAPK), which belongs to serine/threonine kinases, is an important molecule which can receive signals delivered by a receptor and bring the signals into the cell nucleus, has an important mechanism for participating in the regulation of gene expression, cell proliferation and death, and plays a key role in many receptor signaling pathways. P38 kinase, an important member in the mitogen-activated protein kinase (MAPK) family, is considered as an important part of the cell factor-mediated immune response mechanism, the p38 kinase not only plays an important role in inflammatory and stress reaction but also participates in the processes of cell survival, differentiation and apoptosis, therefore, it is considered as an important protein in numerous cell signaling pathways. It is known that p38 kinase can phosphorylate some intracellular proteins, which involve in the cascade of the enzymatic step and can result in the biological synthesis and release of cytokines (such as TNF-α and IL-1). Research finds that p38 kinase has an obvious regulation effect on the occurrence of many diseases, and particularly plays a core role in the regulation of inflammatory response diseases. The inflammatory response is essentially an important component of human autoimmune system, if an exception occurs, a series of serious diseases, such as rheumatoid arthritis, chronic lung obstruction, cardiovascular disease, gout, psoriasis, asthma, tumor, diabetes mellitus, arteriosclerosis, Crohn's disease and the like will be caused.
It is well known that cytokines are produced by a variety of cells (such as single cell and macrophages), which can result in a number of physiological effects, these physiological effects are considered to be very important in diseases (such as inflammation and immunoregulation). Cytokines are also considered to affect the generation and the development of diseases.
Tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1) are two important proinflammatory cytokines, they are considered as the main medium for activating the cell cascade reactions and play a leading role in the systemic inflammatory response, which is described in Charles A. Dinarello et al., inflammatory cytokines: interleukin-1 and tumor necrosis factor as effect or molecules in autoimmune diseases, Current Opinion in Immunology, 1991, 3(6), 941-948. Research shows that when a specific inhibitor acts on the p38 kinase, the expression quantity of the proinflammatory cytokines such as TNF-α and the like is remarkably reduced, this indicates that the over-expression of TNF-α and the like in inflammatory reactions is closely related to the activity of p38 kinase. P38 kinase participates in the inflammatory reaction process by controlling and modulating the synthesis and the release process of proinflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and anti-inflammatory factors such as interleukin-10 and the like. Therefore, cytokines (such as TNF-α and IL-1) are considered to participate in mediating many diseases, and it is expected that the inhibition on the generation and/or the effect of these cytokines may help prevent, control or treat these diseases.
Non-steroidal anti-inflammatory drugs (NSAIDs) are the most common anti-inflammatory drugs, however, many individuals cannot tolerate the dosage required by long-time treatment of the diseases, the use of such drugs often cause serious toxic and side effects, such as the damage of gastrointestinal tract, kidney and liver, and sometimes may induce cardiovascular adverse events. In the biological treatment field of anti-inflammatory cytokines, great successes have been achieved in the use of the biological agents such as Etanercept, Inflimab, Adalimumab, Anakinra and the like for treating inflammatory patients, to whom the non-steroidal anti-inflammatory drugs are ineffective or inconvenient. However, as macromolecular drugs, the biological agents have many defects such as relatively long research period, being difficult to industrialize, relatively high production cost, and being inconvenient to use as an injection preparation and the like, therefore, there is a need for new oral anti-inflammatory drugs which are convenient to use and have good curative effect in the field of anti-inflammatory therapy. Since p38 kinase is considered to be a key anti-inflammatory target, it regulates TNF, IL-1 and other inflammatory factors and plays an important biological role in regulating the inflammatory response, as a small chemical molecule substance, the p38 kinase inhibitor has the potential to be developed into a novel small molecular drug for treating inflammatory diseases. However, poor oral bioavailability and high toxicity have been the main problem in preventing these compounds from becoming drugs.